In the present project, the molecular basis for the antiproliferative activity of agents which interfere with the metabolism and/or function of polyamines will be evaluated. Although the latter molecules are known to be elevated in, and presumably involved in, cell proliferation, their critical significance in this process is not known. Methylglyoxal-bis-(guanylhydrazone) (MGBG), an agent active against solid tumors, will be primarily studied but other drugs having similar actions or bearing structural resemblance to MGBG will be also used. In addition to inhibiting spermidine and spermine biosynthesis, MGBG has a profound effect on the structure and function of mitochondria of normal and tumor cells. It is now known that the mitochondrial effect is unrelated to drug action on polyamine metabolism. The relevance of either drug action to the antiproliferative properties of MGBG is currently being sought. The objectives of this study are: (a) to determine the contribution of MCGB interference with mitochondrial function and with polyamine metabolism to its antiproliferative action (b) to further elucidate the molecular basis for the MGBG-induced mitochondrial effects giving particular attention to possible interaction with polyamines (c) to evaluate mitochondrial function and polyamine metabolism as targets for cancer chemotherapy (d) to determine the relevance of polyamines to cell proliferation. Among the parameters that will be used in assessing drug effects are cell growth kinetics, cell ultrastructural changes, polyamine pool size analysis by high pressure liquid chromatography, oxygen consumption studies of intact cells and isolated mitochondria, pyruvate utilization, synthesis of nuclear DNA by precursor incorporation and ornithine and S-adenosylmethionine decarboxylase activities by biochemical assay.